Chronic myeloid leukemia (CML) was the first cancer for which a specific genetic abnormality was identified, the Philadelphia chromosome (Nowell & Hungerford, “Chromosome Studies on Normal and Leukemic Human Leukocytes,” J. Nat'l. Cancer Inst. 25:85-109 (1960)). Subsequent studies identified that the translocation event occurred between t(9;22)(q34;q11), which fused the breakpoint cluster region gene (BCR) with the Abelson kinase (ABL1) gene to produce the oncogene, Bcr-Abl (Bartram et al., “Translocation of C-abl Oncogene Correlates with the Presence of a Philadelphia Chromosome in Chronic Myelocytic Leukaemia,” Nature 306:277-280 (1983); Druker, B. J., “Translation of the Philadelphia Chromosome Into Therapy for CML,” Blood 112:4808-4817 (2008); Rowley, J. D., “Letter: A New Consistent Chromosomal Abnormality in Chronic Myelogenous Leukaemia Identified by Quinacrine Fluorescence and Giemsa Staining,” Nature 243:290-293 (1973)). This fusion protein possesses constitutive tyrosine kinase activity resulting in development of myeloid leukemia through aberrant differentiation of hematopoietic stem cells (HSC) towards the myeloid lineage. Clinically, CML progresses through at least three different phases: chronic phase (CP), late chronic/accelerated phase (AP) and blast crisis (BC), respectively.
Patients diagnosed with CML in the early chronic phase have been successfully treated with imatinib, which inhibits the tyrosine kinase activity of Bcr-Abl and have a 5-year progression free survival rate of 89% (Druker et al., “Five-Year Follow-Up of Patients Receiving Imatinib for Chronic Myeloid Leukemia,” N. Engl. J. Med. 355:2408-2417 (2006)). However, only a fraction of imatinib-treated patients achieve long-term remission, suggesting that the compound is unable to target CML initiating populations (de Lavallade et al., “Imatinib for Newly Diagnosed Patients With Chronic Myeloid Leukemia: Incidence of Sustained Responses in an Intention-to-Treat Analysis,” J. Clin. Oncol. 26:3358-3363 (2008); Hochhaus et al., “Six-Year Follow-Up of Patients Receiving Imatinib for the First-Line Treatment of Chronic Myeloid Leukemia,” Leukemia 23:1054-1061 (2009)). Indeed, the majority of the patients relapse upon cessation of tyrosine-kinase inhibitor (TKI) treatment (Michor et al., “Dynamics of Chronic Myeloid Leukaemia,” Nature 435:1267-1270 (2005)). Moreover, some patients, particularly the ones that present with advanced disease can develop resistance to Imatinib treatment (O'Hare et al., “Targeted CML Therapy: Controlling Drug Resistance, Seeking Cure,” Curr. Opin. Genet. Dev. 16:92-99 (2006)). The mechanisms thought to drive resistance and disease relapse include the acquisition of mutations in the kinase domain of Bcr-Abl, amplification of Bcr-Abl, and clonal evolution (Gorre et al., “Clinical Resistance to STI-571 Cancer Therapy Caused by BCR-ABL Gene Mutation or Amplification,” Science 293:876-880 (2001); Jabbour et al., “Frequency and Clinical Significance of BCR-ABL Mutations in Patients With Chronic Myeloid Leukemia Treated With Imatinib Mesylate,” Leukemia 20:1767-1773 (2006); le Coutre et al., “Induction of Resistance to the Abelson Inhibitor STI571 in Human Leukemic Cells Through Gene Amplification,” Blood 95:1758-1766 (2000); Shah et al., “Multiple BCR-ABL Kinase Domain Mutations Confer Polyclonal Resistance to the Tyrosine Kinase Inhibitor Imatinib (STI571) in Chronic Phase and Blast Crisis Chronic Myeloid Leukemia,” Cancer Cell 2:117-125 (2002)).
An increasing body of work has suggested that disease relapse upon cessation of TKI therapy could be due to a rare population of leukemia initiating cells (LICs) that are resistant or refractory to treatment (Bhatia et al., “Persistence of Malignant Hematopoietic Progenitors in Chronic Myelogenous Leukemia Patients in Complete Cytogenetic Remission Following Imatinib Mesylate Treatment,” Blood 101:4701-4707 (2003); Corbin et al., “Human Chronic Myeloid Leukemia Stem Cells are Insensitive to Imatinib Despite Inhibition of BCR-ABL Activity,” J. Clin. Invest. 121:396-409 (2011); Graham et al., “Primitive, Quiescent, Philadelphia-Positive Stem Cells From Patients With Chronic Myeloid Leukemia are Insensitive to STI571 In Vitro,” Blood 99:319-325 (2002); Hu et al., “beta-Catenin is Essential for Survival of Leukemic Stem Cells Insensitive to Kinase Inhibition in Mice with BCR-ABL-Induced Chronic Myeloid Leukemia,” Leukemia 23:109-116 (2009)). LICs are thought to possess properties similar to normal hematopoietic stem cells such as self-renewal, quiescence and resistance to traditional chemotherapy (Bonnet & Dick, “Human Acute Myeloid Leukemia is Organized as a Hierarchy That Originates From a Primitive Hematopoietic Cell,” Nat. Med. 3:730-737 (1997); Huntly & Gilliland, “Leukaemia Stem Cells and the Evolution of Cancer-Stem-Cell Research,” Nat. Rev. Cancer 5:311-321 (2005)). Thus, the LIC subset might act as a reservoir contributing to relapse by passing Bcr-Abl on to its progeny, which then mimic the disease. In different types of leukemia, evidence in support of the LIC determined that only a small fraction of acute myeloid leukemia cells from patients were able to recapitulate the disease when transplanted into immuno-compromised animals (Bonnet & Dick, “Human Acute Myeloid Leukemia is Organized as a Hierarchy That Originates From a Primitive Hematopoietic Cell,” Nat. Med. 3:730-737 (1997); Lapidot et al., “A Cell Initiating Human Acute Myeloid Leukaemia After Transplantation Into SCID Mice,” Nature 367:645-648 (1994)). Using similar assays, putative LIC populations were also identified in patients diagnosed with chronic phase and blast crisis CML (Jamieson et al., “Granulocyte-Macrophage Progenitors as Candidate Leukemic Stem Cells In Blast-Crisis CML,” N. Engl. J. Med. 351:657-667 (2004); Sirard et al., “Normal and Leukemic SCID-Repopulating Cells (SRC) Coexist in the Bone Marrow and Peripheral Blood From CML Patients in Chronic Phase, Whereas Leukemic SRC are Detected in Blast Crisis,” Blood 87:1539-1548 (1996); Wang et al., “High Level Engraftment of NOD/SCID Mice by Primitive Normal and Leukemic Hematopoietic Cells From Patients With Chronic Myeloid Leukemia in Chronic Phase,” Blood 91:2406-2414 (1998)).
The development of mouse models, which proved that expression of Bcr-Abl alone is indeed leukemogenic, have provided an important tool to investigate the mechanisms involved in maintaining the LIC subset (Daley et al., “Induction of Chronic Myelogenous Leukemia in Mice by the P210bcr/abl Gene of the Philadelphia Chromosome,” Science 247:824-830 (1990); Heisterkamp et al., “Acute Leukaemia in bcr/abl Transgenic Mice,” Nature 344:251-253 (1990); Pear et al., “Efficient and Rapid Induction of a Chronic Myelogenous Leukemia-Like Myeloproliferative Disease in Mice Receiving P210 bcr/abl-Transduced Bone Marrow,” Blood 92:3780-3792 (1998)). Over the years, the Bcr-Abl oncogene has been shown to contribute to tumorigenesis through deregulation of molecular pathways that control hematopoietic stem cell self-renewal and differentiation (Heidel et al., “Genetic and Pharmacologic Inhibition of Beta-Catenin Targets Imatinib-Resistant Leukemia Stem Cells in CML,” Cell Stem Cell 10:412-424 (2012); Jamieson et al., “Granulocyte-Macrophage Progenitors as Candidate Leukemic Stem Cells In Blast-Crisis CML,” N. Engl. J. Med. 351:657-667 (2004); Nakahara et al., “Hes1 Immortalizes Committed Progenitors and Plays a Role in Blast Crisis Transition in Chronic Myelogenous Leukemia,” Blood 115:2872-2881 (2010); Passegue et al., “JunB Deficiency Leads to a Myeloproliferative Disorder Arising From Hematopoietic Stem Cells,” Cell 119:431-443 (2004); Zhao et al., “Loss of Beta-Catenin Impairs the Renewal of Normal and CML Stem Cells In Vivo,” Cancer Cell 12:528-541 (2007); Zhao et al., “Hedgehog Signalling is Essential for Maintenance of Cancer Stem Cells in Myeloid Leukaemia,” Nature 458:776-779 (2009). Moreover, transplantation studies in mouse models of Bcr-Abl-induced chronic phase CML suggested that LIC activity is confined to Bcr-Abl-expressing LinnegSca1+c-Kit+ (LSK) cells (Neering et al., “Leukemia Stem Cells in a Genetically Defined Murine Model of Blast-Crisis CML,” Blood 110:2578-2585 (2007)).